US8383581B2 - Short-chain peptides as parathyroid hormone (PTH) receptor agonist - Google Patents

Short-chain peptides as parathyroid hormone (PTH) receptor agonist Download PDF

Info

Publication number
US8383581B2
US8383581B2 US13/259,706 US201013259706A US8383581B2 US 8383581 B2 US8383581 B2 US 8383581B2 US 201013259706 A US201013259706 A US 201013259706A US 8383581 B2 US8383581 B2 US 8383581B2
Authority
US
United States
Prior art keywords
aib
phe
nle
eiq
har
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US13/259,706
Other languages
English (en)
Other versions
US20120108496A1 (en
Inventor
Rajesh Bahekar
Mukul R. Jain
Pankaj R. Patel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Assigned to CADILA HEALTHCARE LIMITED reassignment CADILA HEALTHCARE LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAHEKAR, RAJESH, JAIN, MUKUL R., PATEL, PANKAJ R.
Publication of US20120108496A1 publication Critical patent/US20120108496A1/en
Application granted granted Critical
Publication of US8383581B2 publication Critical patent/US8383581B2/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel short-chain peptides as PTH receptor agonist of general formula (I), their pharmaceutically acceptable salts and pharmaceutical compositions containing them.
  • the present invention also relates to processes for preparing compounds of general formula (I), their pharmaceutically acceptable salts and pharmaceutical compositions containing them.
  • Osteoporosis is a skeletal disorder characterised by diminished bone mass, decreased bone mineral density (BMD), decreased bone strength and associated with an increased risk of bone fracture (Lane J. M., et al., Clin. Orthop. Relat. Res., 372, 2000, 139-150). Osteoporotic fractures most often occur in the vertebrae, hips or the femoral neck. These fractures severely impair the quality of life because of pain, long-lasting immobility and poor recovery. Bone comprises of several different cell types. Osteoblast (bone formation) lays down new bone from the mineral present in the extracellular milieu around the cells. Osteoclasts (bone loss) remove old bones, releasing the minerals compiled within bone back into the extracellular matrix.
  • BMD bone mineral density
  • Osteoporosis occurs when the rate of the bone resorption is greater than the rate of bone formation (Seeman E., et al., N. Engl. J. Med., 354(21), 2006, 2250-2261).
  • Postmenopausal estrogen deficiency is the most common cause of osteoporosis in women, as estrogen puts a break on osteoclast lifespan.
  • Other major risk factors in the development of osteoporosis include: low calcium intake, vitamin D deficiency, type-1 diabetes, rheumatoid arthritis, long-term use of medication such as anticonvulsants and corticosteroids and low levels of testosterone in men (Cole Z. A., et al., Curr. Rheumatol. Rep., 10(2), 2008, 92-96; Harvey, N., et al., Cliff. Rheumatol. Rep., 5(1), 2003, 75-81).
  • PTH Native human Parathyroid Hormone
  • PTH in-turn, maintains the serum calcium level by directly or indirectly promoting calcium entry into the blood.
  • PTH contributes to net gastrointestinal absorption of calcium by favouring the renal synthesis of the active form of vitamin D.
  • PTH promotes calcium reabsorption from bone, indirectly by stimulating differentiation of the osteoclasts (bone-resorbing cells).
  • Administration of PTH via parenteral route efficiently increases bone mineral density (BMD), bone strength and reduces the incidence of new osteoporotic fractures in osteoporotic patients (Greenspan S. L., et al., Ann. Intern. Med., 146(5), 2007, 326-339; Neer R. M., et al., N. Engl. J. Med., 344, 2001, 1434-1441).
  • PTH exerts all these effects primarily through its interaction with a cell surface PTH receptor, which is expressed in numerous tissues, most abundantly in kidney, bone and growth plate chondrocytes (Lanske B., et al., Crit. Rev. Eukaryot. Gene Expr., 8, 1998, 297-320).
  • the PTH receptor is homologous in primary structure to a number of other receptors that bind peptide hormones, such as secretin, calcitonin and glucagon; together, these receptors form a distinct family called G-protein coupled receptors (GPCR/GPCRs) family B (Kolakowski L. F., Receptor Channels, 2, 1994, 1-7).
  • the GPCR comprise an extracellular N-terminal domain of 100-160 residues, connected to a juxtamembrane domain (J-domain) of seven membrane-spanning ⁇ -helices with intervening loops and a C-terminal tail (Donnelly D., FEBS Letts., 409, 1997, 431-436).
  • J-domain juxtamembrane domain
  • the Class B GPCRs are activated by endogenous peptide ligands of intermediate size, typically 30-40 amino acids (Hoare, S. R. J., Drug. Discovery Today, 10, 2005, 423-427). A general mechanism of peptide ligand interaction with class B GPCRs has emerged and is termed as the ‘two-domain’ model.
  • the C-terminal portion of the peptide binds the N-domain of the receptor, confirm binding of ligand with the receptor and the N-terminal ligand region binds the J-domain, an interaction that activates the receptor and stimulates intracellular signaling (Ji T. H., et al., J. Biol. Chem.; 273, 1988, 17299-17302; Hjorth, S. A., et al., Regulatory Peptides, 64, 1996, 70).
  • PTH binds to the PTH receptor with affinity in the nM range; the ligand-occupied receptor transmits a signal across the cell membrane to intracellular effector enzymes through a mechanism that involves intermediary heterotrimeric GTP-binding proteins (G proteins).
  • G proteins GTP-binding proteins
  • the primary intracellular effector enzyme activated by the PTH receptor in response to PTH peptide is adenylyl cyclase (AC) (Goltzman D., J. Bone Miner. Res., 15(3), 2000, 605-608).
  • cAMP cyclic adenosine monophosphate
  • Other signalling pathways of this receptor such as elevation of intracellular calcium, phospholipase C-dependent and independent activation of protein kinase C, have been described.
  • the parathyroid hormone and its derivatives represent potential therapeutic agent for the treatment of osteoporosis (Slovik D. M., et al., J. Bone Miner. Res., 1, 1986, 377-381; Dempster D. W., et al., Endocr. Rev., 14, 1993, 690-709).
  • Synthetic PTH (1-34) exhibits full bioactivity in most cell-based assay systems, has potent anabolic effects on bone mass in animals and has recently been shown to reduce the risk of bone fracture in postmenopausal osteoporotic women.
  • daily subcutaneous injections of low doses of PTH (1-34) were shown to result in impressive bone formation in the spine and femoral neck with significant reduction in incidence of vertebral fractures (Neer R. M., et al., N. Engl. J. Med., 344, 2001, 1434-1441; Dempster D. W., et al., Endocr. Rev., 14, 1993, 690-709).
  • PTH as one of the most efficacious agents tested for osteoporosis. Under the brand name Forteo (Eli Lilly), PTH (1-34) in the form of teriparatide acetate has been approved for the treatment of osteoporosis.
  • PTH derivatives include polypeptides that have amino acid substitutions or are truncated relative to the full-length molecule. Both the N and C-terminal truncated forms of PTH (1-34) has been studied. Additionally, amino acid substitutions within the truncated polypeptides have also been investigated. (Azurani A., et al., J. Biol. Chem., 271, 1996, 14931-14936). It has been known that residues in the 15-34 domain of PTH peptide contribute importantly to receptor binding affinity, while N-terminal 1-14 amino acids of PTH peptide are responsible for the activation of receptor (Naussbaum S. R., et al., J. Biol.
  • Truncated PTH (1-34) derivatives such as cyclised PTH (1-17), PTH (1-28) and PTH (1-31) are active in most assay systems and promote bone-formation (Whitfield J.
  • PTH is highly susceptible to protease attack and must be stored at low temperature due to its low stability.
  • tolerability is limited by transient mobilization of calcium and hypercalcemia also the toxicological data and in particular the unfavourable results of cancerogenesis studies (dose and treatment duration dependent increased risk of osteosarcoma) induce a cautious use of PTH (1-34) (Vahle J. L., Toxicol. Pathos., 32(4), 2004, 426-438; Whitfield J.
  • PTH(1-11) analogs [Ala 3 , Gln 10 , Arg 11 ]-PTH(1-11), [Ala 3 , Gln 10 , Har 11 ]-PTH(1-11) and [Aib 1,3 ; Gln 10 ; Har 11 ]-PTH(1-11)
  • PTH (1-14) analogs such as [AC 5 C 1 , Aib 3 , Gln 10 , Har 11 , Ala 12 , Trp 14 ]PTH(1-14) stimulate cAMP, in nM range (WO 03/009804; WO 04/093902).
  • PTH parathyroid hormone peptide
  • Xaa1 and Xaa3 represent either Aib or AC 5 C
  • Xaa8 represent Nle
  • Xaa10 represent Q
  • Xaa11 represent Har
  • Xaa12 represent Ala
  • Xaa14 represent W
  • WO 03/009804 A2 US 2006/7153951 B2; US 2007/0117157 A1; US 2007/0203071 A1; US 2006/0019902 A1; US 2007/0161569 A1; US 2007/0111946 A1; Gardella T. J., et al., J. Biol. Chem. 2000, 275, 21836-21843; Gardella T.
  • the present invention describes a group of novel short-chain peptides that function as agonist of the PTH receptor, having different degree of affinity towards the PTH/PTH-1 receptor and useful for the treatment of osteoporosis.
  • These short-chain peptides are defined by the general formula (I) as given below.
  • the short-chain peptides of the present invention are useful for the treatment or prevention of hypoparathyroidism and diseases characterized by bone mass reduction or bone loss, such as osteoporosis, postmenopausal osteoporosis and for stimulating bone repair.
  • the present invention provides novel short-chain peptides of formula (I), which primarily act as a PTH/PTH-1 receptor agonist. These short-chain peptides exhibit increased metabolic stability against proteolytic enzymes. Most of short-chain peptides were found to be stable in rat plasma up to 24 hours (in vitro), showed increased stability against GIT enzymes such as pepsin and acidic stomach pH and also against liver microsomes (in vitro). Due to increased metabolic stability, other than parenteral route of administration, some of these short-chain peptides can also be delivered by oral route of administration.
  • a preferred embodiment of the present invention is to provide novel short-chain peptides of general formula (I), novel intermediates involved in their synthesis, their pharmaceutically acceptable salts and pharmaceutical compositions containing them or their mixtures, suitable for the treatment/mitigation/regulation of bone disorders.
  • compositions containing short-chain peptides of general formula (I), their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture are provided.
  • novel short-chain peptides of the present invention as agents for stimulating new bone formation and treating and/or preventing osteoporosis and related bone disorders, by administering a therapeutically effective and non-toxic amount of the short chain peptides of formula (I), or their pharmaceutically acceptable compositions to the mammals those are in need of such treatment.
  • Aib ⁇ -Amino-isobutyric acid
  • ⁇ -Me-APPA 2-amino-2-methyl-5-phenylpentanoic acid
  • ⁇ -Me-2F-Phe alpha-methyl-2-fluorophenylalanine
  • ⁇ -Me-2,6-F-Phe alpha-methyl-2,6-difluorophenylalanine
  • ⁇ Me-Trp alpha-methyl-Tryptophan
  • cAMP Adenosine 3′,5′-cyclic monophosphate
  • DIPCDI Di-isopropylcarbodiimide
  • DIPEA Diisopropylethylamine
  • Fmoc Fluorenylmethoxycarbonyl
  • HOBt 1-Hydroxybenzotriazole
  • HBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl aminium hexafluorophosphate
  • Orn Ornithine
  • PTH Parathyroid Hormone
  • PTH-1r agonist Parathyroid Hormone receptor agonist
  • PyBOP Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
  • TIPS Triisopropylsilane
  • TBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate
  • Trt Trityl group
  • Trp Tryptophan
  • FIG. 1 In vitro DRC and EC 50 determination of PTH(1-34) (FIG. A) and Seq. ID No. 111 (FIG. B), in Rat PTH-1 R assay (agonistic activity, measured by amount of cAMP released).
  • FIG. 2 Examples of orthogonally protected amino acids used in Fmoc based-solid phase peptide synthesis (SPPS) of short-chain peptides.
  • SPPS Fmoc based-solid phase peptide synthesis
  • FIG. 3 In vivo DRC study with Seq. ID No. 111 (FIG. A: % increase in serum Ca 2+ levels; FIG. B: % decrease in serum PO 4 levels), in OVX Female Rat.
  • FIG. 4 Changes in biochemical parameters and femur weight, in OVX Rat after 6 weeks treatment with Seq. ID No. 111 and PTH(1-34).
  • FIG. 5 Histological sections of the femur, in OVX rats after 6 weeks treatment with Seq. ID No. 111.
  • FIG. 6 Histological sections of the tibia in OVX rats after 6 weeks treatment with Seq. ID No. 111.
  • FIG. 7 Histological sections of the lumbar vertebrae in OVX rats after 6 weeks treatment with Seq. ID No. 111.
  • synthetic short-chain peptides having the structural formula (I), which showed PTH-1 receptor agonistic activity are disclosed.
  • These short-chain peptides exhibit increased metabolic stability to proteolytic cleavage, as most of short-chain peptides were found to be stable in rat plasma up to 24 hours (in vitro), showed increased stability against GIT enzymes such as pepsin and acidic stomach pH and also against liver microsomes (in vitro).
  • GIT enzymes such as pepsin and acidic stomach pH and also against liver microsomes (in vitro).
  • some of these short-chain peptides can also be delivered by oral routes of administration, for the treatment/prevention of hypoparathyroidism and diseases characterized by bone mass reduction, such as osteoporosis, postmenopausal osteoporosis and for stimulating bone repair.
  • the present invention thus discloses novel short-chain peptides as PTH receptor agonist having the following structure (I) A-Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -B (I) wherein, ‘A’ represents the groups —NH—R 1 or R 3 —CO—NH—, wherein R 1 represents hydrogen, Biotin, or optionally substituted linear or branched (C 1-18 ) alkyl chain, or suitable amino acids such as pyroglutamic acid (Pyr), Pro (P), alpha-methyl-Proline ( ⁇ Me-P), Val (V), N-methyl-valine (NMe-V), alpha-methyl-Valine ( ⁇ Me-V), Lys(Biotin), Lys(alkyl), Lys(acetyl); R 3 is selected from optionally substituted linear or branched (C
  • the aryl group is selected from phenyl, napthyl, indanyl, fluorenyl or biphenyl, groups; the heteroaryl group is selected from pyridyl, thienyl, furyl, imidazolyl, benzofuranyl groups; the arylalkyl groups represent groups wherein the aryl group is attached to an alkyl groups as defined elsewhere in the specification.
  • ‘B’ represents —COOR 2 , —CONHR 2 or CH 2 OR 2 , wherein R 2 represents H or suitable amino acids such as Val (V), alpha-methyl-Valine ( ⁇ Me-V), Lys(Biotin), Lys(alkyl), Lys(acetyl) and the like;
  • Each of Z 1 , Z 3 & Z 12 may be same or different and independently represents naturally or unnaturally occurring amino acids selected from the group comprising of Ser (S), alpha-methyl-Serine ( ⁇ Me-S), Val (V), alpha-methyl-Valine ( ⁇ Me-V), Pro (P), alpha-methyl-Proline ( ⁇ Me-P), Gly (G), Ala (A), ⁇ -amino-isobutyric acid (Aib), 1-amino cyclopropane carboxylic acid (AC 3 C), 1-amino-cyclopentanecarboxylic acid (AC 5 C), 1-amino-cyclohexanecarboxylic acid (AC 6 C);
  • Z 2 represents either a Val (V) or ⁇ Me-Val ( ⁇ Me-V);
  • Each of Z 4 , Z 6 & Z 10 may be same or different and independently represents a naturally or unnaturally occurring amino acid selected from the group comprising of Glu (E), Homoglutamic acid (HoGlu), 2-amino-4-cyanobutanoic acid (Abu(CN)), Asp(D), Asn(N), Gln(Q), Aib;
  • Each of Z 5 , Z 7 & Z 9 may be same or different and independently represents a naturally or unnaturally occurring amino acid selected from the group comprising of Leu (L), Ile (I), Nle (Norleucine), Nva (Norvaline), HoLeu (Homoleucine), Abu(CN), His (H), Phe (F), alpha-methyl-phenylalanine (- ⁇ -Me-Phe-), alpha-methyl-2-fluorophenylalanine (- ⁇ -Me-2F-Phe-) or alpha-methyl-2,6-difluorophenylalanine (- ⁇ -Me-2,6-F-Phe-) or 2-fluorophenylalanine (-2F-Phe-) as below;
  • Z 8 represents a naturally or unnaturally occurring amino acid selected from the group comprising of Met, N-methyl-Met ((NMe)M), alpha-methyl-Met ( ⁇ Me-M), alpha-methyl-Valine ( ⁇ Me-V), Leu, Nle, N-methyl-Nle ((NMe)Nle), alpha-methyl-Norleucine ( ⁇ Me-Nle), Nva, HoLeu, Ethionine (EtMet), selenomethionine (SMet), Val;
  • Z 11 and Z 13 may be same or different and independently represents a naturally or unnaturally occurring amino acid selected from the group comprising of Aib, Pro (P), ⁇ Me-Pro, Lysine (K), Lysine-Biotin (K(Biotin)), Lysine(Nitro); K(NO 2 ), Arginine (R), Arginine(Nitro); (Arg(NO 2 )), Homoarginine (Har), Ornithine (Orn), Ornithine(Nitro); Orn(NO 2 ), Citrulline (Cit), Homocitrulline (HoCit), Phe (F), alpha-methyl-phenylalanine (- ⁇ -Me-Phe-), alpha-methyl-2-fluorophenylalanine (- ⁇ -Me-2F-Phe-) or alpha-methyl-2,6-difluorophenylalanine (- ⁇ -Me-2,6-F-Phe-) or 2-fluoroph
  • Z 14 represents a naturally or unnaturally occurring amino acid selected from the group comprising of 2′-ethyl-4′-methoxy-biphenylalanine (Bip(OMe)), ⁇ -methylated Bip(OMe) [ ⁇ Me-Bip(OMe)], ⁇ Me-Trp, alpha-methyl-phenylalanine (- ⁇ -Me-Phe-), alpha-methyl-2-fluorophenylalanine (- ⁇ -Me-2F-Phe-), alpha-methyl-2,6-difluorophenylalanine (- ⁇ -Me-2,6-F-Phe-) or 2-fluorophenylalanine (-2F-Phe-) as below:
  • Z 15 may be present or absent.
  • Z 15 when present represents a naturally or unnaturally occurring amino acid selected from the group comprising of 2-amino-5-phenylpentanoic acid (APPA) or 2-amino-2-methyl-5-phenylpentanoic acid ( ⁇ -Me-APPA);
  • APPA 2-amino-5-phenylpentanoic acid
  • ⁇ -Me-APPA 2-amino-2-methyl-5-phenylpentanoic acid
  • R 3 is selected from optionally substituted linear or branched (C 1-18 ) alkyl chain and all other symbols are as defined earlier;
  • each of Z 1 , Z 3 & Z 12 may be same or different and independently represents naturally or unnaturally occurring amino acids selected from the group comprising of Ala (A), ⁇ -amino-isobutyric acid (Aib), 1-amino cyclopropane carboxylic acid (AC 3 C), 1-amino-cyclopentanecarboxylic acid (AC 5 C), 1-amino-cyclohexanecarboxylic acid (AC 6 C) and all other symbols are as defined earlier;
  • each of Z 4 , Z 6 & Z 10 may be same or different and independently represents a naturally or unnaturally occurring amino acid selected from the group comprising of Glu (E), Gln (Q), Aib and all other symbols are as defined earlier;
  • each of Z 5 , Z 7 & Z 9 may be same or different and independently represents a naturally or unnaturally occurring amino acid selected from the group comprising of Leu (L), Ile (I), Nle, HoLeu (Homoleucine), His (H), alpha-methyl-2-fluorophenylalanine (- ⁇ -Me-2F-Phe-), alpha-methyl-2,6-difluorophenylalanine (- ⁇ -Me-2,6-F-Phe-) and all other symbols are as defined earlier;
  • Z 8 represents a naturally or unnaturally occurring amino acid selected from the group comprising of Met, alpha-methyl-Met ( ⁇ Me-M), Nle, N-methyl-Nle ((NMe)Nle) and all other symbols are as defined earlier;
  • each of Z 11 and Z 13 may be same or different and independently represents a naturally or unnaturally occurring amino acid selected from the group comprising of Aib, ⁇ Me-Pro, Lysine (K), Lysine-Biotin (K(Biotin)), K(NO 2 ), Arginine (R), Arg(NO 2 ), Homoarginine (Har), Ornithine (Orn), Orn(NO 2 ), Citrulline (Cit), Homocitrulline (HoCit), alpha-methyl-2-fluorophenylalanine (- ⁇ -Me-2F-Phe-), alpha-methyl-2,6-difluorophenylalanine (- ⁇ -Me-2,6-F-Phe-) and all other symbols are as defined earlier;
  • Z 14 represents a naturally or unnaturally occurring amino acid selected from the group comprising of 2′-ethyl-4′-methoxy-biphenylalanine (Bip(OMe)), ⁇ -methylated Bip(OMe) [ ⁇ Me-Bip(OMe)], alpha-methyl-2-fluorophenylalanine (- ⁇ -Me-2F-Phe-), alpha-methyl-2,6-difluorophenylalanine (- ⁇ -Me-2,6-F-Phe-) and all other symbols are as defined earlier;
  • Z 15 is present and represents naturally or unnaturally occurring amino acid selected from the group comprising of 2-amino-5-phenylpentanoic acid (APPA) or 2-amino-2-methyl-5-phenylpentanoic acid ( ⁇ -Me-APPA);
  • APPA 2-amino-5-phenylpentanoic acid
  • ⁇ -Me-APPA 2-amino-2-methyl-5-phenylpentanoic acid
  • the present invention discloses modified PTH analogues of formula (I) wherein ‘A’ represents the groups —NH—R 1 or R 3 —CO—NH—, wherein R 1 represents hydrogen, Biotin or suitable amino acids such as pyroglutamic acid (Pyr), Pro (P), Val (V); R 3 is selected from optionally substituted linear or branched (C 1-18 ) alkyl chain; ‘B’ represents —COOR 2 , —CONHR 2 wherein R 2 is as defined earlier; each of Z 1 , Z 3 & Z 12 may be same or different and independently represents a naturally or unnaturally occurring amino acids selected from the group comprising of Ala (A), ⁇ -amino-isobutyric acid (Aib), 1-amino cyclopropane carboxylic acid (AC 3 C), 1-amino-cyclopentanecarboxylic acid (AC 5 C), 1-amino-cyclohexanecarboxylic acid (AC 6 C); Z 2
  • substituents on any of the groups defined above may be selected from hydroxyl, oxo, halo, thio, nitro, amino, alkyl, alkoxy, haloalkyl or haloalkoxy groups;
  • natural amino acids indicates all those twenty amino acids, which are present in nature.
  • unnatural amino acids or ‘non-natural amino acids’ preferably represents either replacement of L-amino acids with corresponding D-amino acids such as replacement of L-Ala with D-Ala and the like or suitable modifications of the L or D amino acids, amino alkyl acids, either by
  • alkyl used herein, either alone or in combination with other radicals, denotes a linear or branched radical containing one to eighteen carbons, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, iso-hexyl, heptyl, octyl, decyl, tetradecyl, octadecyl and the like.
  • cycloalkyl used herein, either alone or in combination with other radicals, denotes a radical containing three to seven carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • amino acid as employed herein alone or as part of another group includes, without limitation, an amino group and a carboxyl group linked to the same carbon, referred to as ‘ ⁇ ’ carbon.
  • the absolute ‘S’ configuration at the ‘ ⁇ ’ carbon is commonly referred to as the ‘L’ or natural configuration.
  • the ‘R’ configuration at the ‘ ⁇ ’ carbon is commonly referred to as the
  • amino acids are Gly or Aib and are not chiral.
  • the compounds of the invention include peptide amides and non-amides and peptide analogues, including but not limited to the following:
  • PTH receptor modulator or agonist refers to a compound that acts at the PTH-1 and/or PTH-2 receptor to alter its ability to regulate downstream signaling events, such as cAMP production.
  • Example of receptor modulators includes agonist, partial agonist, inverse agonist and allosteric potentiators.
  • the synthetic isolated short-chain peptides described herein primarily acts as PTH receptor agonists.
  • These synthetic short-chain peptides exhibit desirable in vitro PTH receptor agonist activity in UMR-106 cells, in the range of 1-1000 nM concentration. PTH receptor agonistic activity is assessed by estimation of amount of cAMP released by the test compounds.
  • Some of the short-chain peptides prepared showed increase in BMD and/or bone strength, when tested in vivo, in OVX rat model, thus making them ideal therapeutic candidates for the treatment and prevention of osteoporosis.
  • These new classes of short-chain peptides can be administered by oral or other non-invasive routes or parenteral routes of administration.
  • the present invention provides short-chain peptides of formula (I) pharmaceutical compositions employing such short-chain peptides either alone or in combination and for methods of using such short-chain peptides.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of short-chain peptides of formula (I), alone or in combination(s), with a pharmaceutically acceptable carrier.
  • osteoporosis especially primary osteoporosis, endocrine osteoporosis, postmenopausal osteoporosis, hereditary and congentinal forms of osteoporosis, wherein, therapeutically effective amount of short-chain peptides of formula (I) or their combination(s) can be administered to a mammal, example, human and a patient in need of treatment.
  • short-chain peptides of the present invention can be synthesized using the methods described below, together with conventional techniques known to those skilled in the art of peptide synthesis, or variations thereon as appreciated by those skilled in the art. Referred methods include, but not limited to those described below.
  • the short-chain peptides thereof described herein may be produced by chemical synthesis using suitable variations of both the solution-phase (preferably, using Boc-chemistry; M. Bodansky, A. Bodansky, “The practice of peptide synthesis”, Springer-Verlag, Berlim, 1984; E. Gross, J. Meinhofer, “The peptide synthesis, analysis, biology”, Vol. 1, Academic Press, London, 1979) and or solid-phase techniques, such as those described in G. Barany & R. B. Merrifield, “The peptides: Analysis, synthesis, Biology”; Volume 2—“Special methods in peptide synthesis, Part. A”, pp. 3-284, E. Gross & J. Meienhofer, Eds., Academic Press, New York, 1980; and in J. M. Stewart and J. D. Young, “Solid-phase peptide synthesis” 2nd Ed., Pierce chemical Co., Rockford, Il, 1984.
  • the preferred strategy for preparing the short-chain peptides of this invention is based on the use of Fmoc-based SPPS approach, wherein Fmoc (9-fluorenylmethoxycarbonyl) group is used for temporary protection of the ⁇ -amino group, in combination with the acid labile protecting groups, such as tert-butoxycarbonyl (Boc), tert-butyl (Bu t ), Trityl (Trt) groups ( FIG. 2 ), for temporary protection of the amino acid side chains, if present (see for example E. Atherton & R. C.
  • the short-chain peptides can be synthesized in a stepwise manner on an insoluble polymer support (resin), starting form the C-terminus of the peptide.
  • the synthesis is initiated by appending the C-terminal amino acid of the peptide to the resin through formation of an amide, ester or ether linkage. This allows the eventual release of the resulting peptide as a C-terminal amide, carboxylic acid or alcohol, respectively.
  • the C-terminal amino acid and all other amino acids used in the synthesis are required to have their ⁇ -amino groups and side chain functionalities (if present) differentially protected (orthogonal protection), such that the ⁇ -amino protecting group may be selectively removed during the synthesis, using suitable base such as 20% piperidine solution, without any premature cleavage of peptide from resin or deprotection of side chain protecting groups, usually protected with the acid labile protecting groups.
  • the coupling of an amino acid is performed by activation of its carboxyl group as an active ester and reaction thereof with unblocked ⁇ -amino group of the N-terminal amino acid appended to the resin. After every coupling and deprotection, peptidyl-resin was washed with the excess of solvents, such as DMF, DCM and diethyl ether. The sequence of ⁇ -amino group deprotection and coupling is repeated until the desired peptide sequence is assembled (Scheme 1). The peptide is then cleaved from the resin with concomitant deprotection of the side chain functionalities, using an appropriate cleavage mixture, usually in the presence of appropriate scavengers to limit side reactions. The resulting peptide is finally purified by reverse phase HPLC.
  • the synthesis of the peptidyl-resins required as precursors to the final peptides utilizes commercially available cross-linked polystyrene polymer resins (Novabiochem, San Diego, Calif.).
  • Preferred for use in this invention is Fmoc-PAL-PEG-PS resin, 4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methyl benzhydrylamine resin (Fmoc-Rink amide MBHA resin), 2-chloro-Trityl-chloride resin or p-benzyloxybenzyl alcohol resin (HMP resin) to which the C-terminal amino acid may or may not be already attached.
  • Fmoc-PAL-PEG-PS resin 4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methyl benzhydrylamine resin
  • the C-terminal amino acid is not attached, its attachment may be achieved by HOBt active ester of the Fmoc-protected amino acid formed by its reaction with DIPCDI.
  • HOBt active ester of the Fmoc-protected amino acid formed by its reaction with DIPCDI.
  • 2-Chloro-trityl resin coupling of first Fmoc-protected amino acid was achieved, using DIPEA.
  • N-terminal protection of peptidyl resin was selectively deprotected using 10-20% piperidine solution. After every coupling and deprotection, excess of amino acids and coupling reagents were removed by washing with DMF, DCM and ether.
  • Coupling of the subsequent amino acids can be accomplished using HOBt or HOAT active esters produced from DIPCDI/HOBt or DIPCDI/HOAT, respectively.
  • HOBt or HOAT active esters produced from DIPCDI/HOBt or DIPCDI/HOAT, respectively.
  • complete coupling can be achieved using a combination of highly efficient coupling agents such as HBTU, PyBOP or TBTU, with additives such as DIPEA.
  • the synthesis of the short-chain peptides described herein can be carried out by using batchwise or continuous flow peptide synthesis apparatus, such as CS-Bio or AAPPTEC peptide synthesizer, utilizing the Fmoc/t-butyl protection strategy.
  • the non-natural non-commercial amino acids present at different position were incorporated into the peptide chain, using one or more methods known in the art.
  • Fmoc-protected non-natural amino acid was prepared in solution, using appropriate literature procedures.
  • the Fmoc-protected APPA analogs, described above were prepared from L-pyroglutamic acid, in good enantiomeric purity, using modified literature procedure (Betsbrugge J. V., et al., Tetrahedron, 54, 1988, 1753-1762).
  • the Fmoc-protected ⁇ -methylated amino acids were prepared using asymmetric Strecker synthesis (Boesten, W. H. J., et al., Org. Lett., 3(8), 2001, 1121-1124; Cativiela C., Diaz-de-villegas M. D., Tetrahedran Asymmetry, 9, 1988, 3517-3599).
  • the resulting derivative was then used in the step-wise synthesis of the peptide.
  • the required non-natural amino acid was built on the resin directly using synthetic organic chemistry procedures and a linear peptide chain were build.
  • the peptide-resin precursors for their respective short-chain peptides may be cleaved and deprotected using suitable variations of any of the standard cleavage procedures described in the literature (King D. S., et al., Int. J. Peptide Protein Res., 1990, 36, 255-266).
  • a preferred method for use in this invention is the use of TFA cleavage mixture, in the presence of water and TIPS as scavengers.
  • the peptidyl-resin was incubated in TFA/Water/TIPS (95:2.5:2.5) for 1.5-4 hrs at room temperature.
  • the cleaved resin is then filtered off and the TFA solution is concentrated or dried under reduced pressure.
  • the resulting crude peptide is either precipitated or washed with Et 2 O or is re-dissolved directly into DMF or 50% aqueous acetic acid for purification by preparative HPLC.
  • Short-chain peptides with the desired purity can be obtained by purification using preparative HPLC.
  • the solution of crude peptide is injected into a semi-Prep column (Luna 10 ⁇ ; C 18 ; 100 A o ), dimension 250 ⁇ 50 mm and eluted with a linear gradient of ACN in water, both buffered with 0.1% TFA, using a flow rate of 40 mL/min with effluent monitoring by PDA detector at 220 nm.
  • the structures of the purified short-chain peptides can be confirmed by Electrospray Mass Spectroscopy (ES-MS) analysis.
  • ES-MS Electrospray Mass Spectroscopy
  • peptide prepared were isolated as trifluoro-acetate salt, with TFA as a counter ion, after the Prep-HPLC purification.
  • some peptides were subjected for desalting, by passing through a suitable ion exchange resin bed, preferably through anion-exchange resin Dowex SBR P(Cl) or an equivalent basic anion-exchange resin.
  • TFA counter ions were replaced with acetate ions, by passing through suitable ion-exchange resin, eluted with dilute acetic acid buffer.
  • selected peptides, with the acetate salt was treated with 4 M HCl.
  • the linear short-chain peptide, H 2 N-(AC 5 C)-V-(AC 5 C)-EIQLMHQ-Har-( ⁇ Me-Pro)-K-( ⁇ -Me-Phe)-PAL-PEG-PS was assembled on an automated CS-Bio 536 PepSynthesiserTM using Fmoc solid phase peptide synthesis (SPPS) approach (Scheme 2).
  • SPPS Fmoc solid phase peptide synthesis
  • the Fmoc amino acids and the 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU) were packed together in vials and positioned in the amino acid module of the synthesizer.
  • a stock solution of diisopropylethylamine (DIPEA; 0.9 M) and DMF were stored in reagent bottles, under dry nitrogen atmosphere.
  • the resin, Fmoc-PAL-PEG-PS (0.38 mmol/g; 1 g) was dried over P 2 O 5 , in vacuo (1 hr) and swollen in freshly distilled DMF (5 mL). The swollen resin was slurry packed into a glass column and positioned in the synthesizer. All the synthetic cycles were carried out at a flow rate of 5 mL min ⁇ 1 , Table 1.
  • the resin was washed with freshly distilled DMF for 10 minutes.
  • Deprotection of Fmoc group was performed with 20% piperidine in DMF for 10 minutes and the deprotection was monitored by UV detection of the column effluent at 304 nm.
  • Ninhydrin resin test was carried out to check the N-terminal free amino group of resin bound peptide. Appearance of blue-purple colouration of the solution and the resin beads indicates the presence of free amino group on resin bound peptide and was considered to be a positive test.
  • the aqueous layer was separated and freeze-dried to yield the crude peptide H 2 N-(AC 5 C)-V-(AC 5 C)-EIQLMHQ-Har-( ⁇ Me-Pro)-K-( ⁇ -Me-Phe)-CONH 2 .
  • the lyophilised peptide H 2 N-(AC 5 C)-V-(AC 5 C)-EIQLMHQ-Har-( ⁇ Me-Pro)-K-( ⁇ -Me-Phe)-CONH 2 was dissolved in 0.1% aqueous TFA (ca 1 mg/1 mL) and its purity was analyzed by analytical RP-HPLC and characterized by electrospray ionisation mass spectrometry (ESI-MS).
  • short-chain peptides designed in the present invention were prepared, using Fmoc-SPPS approach. Furthermore, resin bound short-chain peptides were cleaved and deprotected, purified and characterized using following protocol.
  • the desired short-chain peptides were cleaved and deprotected from their respective peptidyl-resins by treatment with TFA cleavage mixture as follows.
  • a solution of TFA/Water/Triisopropylsilane (95:2.5:2.5) (10 mL/100 mg of peptidyl-resin) was added to peptidyl-resins and the mixture was kept at room temperature with occasional starring.
  • the resin was filtered, washed with a cleavage mixture and the combined filtrate was evaporated to dryness. Residue obtained was dissolved in 10 mL of water and the aqueous layer was extracted 3 times with ether (20 mL each) and finally the aqueous layer was freeze-dried.
  • Crude peptide obtained after freeze-drying was purified by preparative HPLC as follows:
  • Preparative HPLC was carried out on a Shimadzu LC-8A liquid chromatograph.
  • a solution of crude peptide dissolved in DMF or water was injected into a semi-Prep column (Luna 10 ⁇ ; C 18 ; 100 A 0 ), dimension 250 ⁇ 50 mm and eluted with a linear gradient of ACN in water, both buffered with 0.1% TFA, using a flow rate of 15-50 mL/min, with effluent monitoring by PDA detector at 220 nm.
  • a typical gradient of 20% to 70% of water-ACN mixture, buffered with 0.1% TFA was used, over a period of 50 minutes, with 1% gradient change per minute.
  • the desired product eluted were collected in a single 10-20 mL fraction and pure short-chain peptides were obtained as amorphous white powders by lyophilisation of respective HPLC fractions.
  • each peptide was analyzed by analytical RP-HPLC on a Shimadzu LC-LOAD analytical HPLC system.
  • analytical HPLC analysis of short-chain peptides Luna 5 ⁇ ; C 18 ; 100 A o , dimension 250 ⁇ 4.6 mm column was used, with a linear gradient of 0.1% TFA and ACN buffer and the acquisition of chromatogram was carried out at 220 nm, using a PDA detector.
  • Each peptide was characterized by electrospray ionisation mass spectrometry (ESI-MS), either in flow injection or LC/MS mode.
  • ESI-MS electrospray ionisation mass spectrometry
  • Triple quadrupole mass spectrometers API-3000 (MDS-SCIES, Canada) was used in all analyses in positive and negative ion electrospray mode. Full scan data was acquired over the mass range of quadrupole, operated at unit resolution. In all cases, the experimentally measured molecular weight was within 0.5 Daltons of the calculated monoisotopic molecular weight. Quantification of the mass chromatogram was done using Analyst 1.4.1 software. Utilizing the synthetic methods described herein along with other commonly known techniques and suitable variations thereof, the following novel short chain peptides were prepared [Table 2 (i-xix)].
  • Seq. ID. 56 00 (>24) 00 (>24) 00 (>24) 32 (5) Seq. ID. 62 00 (>24) 00 (>24) 00 (>24) 33 (5) Seq. ID. 75 78 (9) 100 (0.5) 100 (0.5) 100 (0.5) Seq. ID. 85 77 (9) 100 (0.5) 100 (0.5) 100 (0.5) Seq. ID. 95 80 (9) 100 (0.5) 100 (0.5) 100 (0.5) Seq. ID. 100 00 (>24) 49 (4) 00 (>24) 82 (2) Seq. ID. 115 78 (8) 12 (8) 55 (6) 79 (1) Seq. ID.
  • Seq. ID. 880 00 (>24) 00 (>24) 00 (>24) 31 (5) Seq. ID. 890 00 (>24) 00 (>24) 00 (>24) 32 (5) Seq. ID. 895 00 (>24) 00 (>24) 00 (>24) 33 (5) Seq. ID. 898 00 (>24) 00 (>24) 26 (5) Seq. ID. 906 78 (9) 100 (0.5) 100 (0.5) 100 (0.5) Seq. ID. 910 77 (9) 100 (0.5) 100 (0.5) 100 (0.5) Seq. ID. 915 80 (9) 100 (0.5) 100 (0.5) 100 (0.5) Seq. ID.
  • Seq. ID. 930 00 (>24) 00 (>24) 00 (>24) 32 (5) Seq. ID. 936 00 (>24) 52 (4) 00 (>24) 81 (2) Seq. ID. 939 10 (>20) 08 (>22) 09 (>22) 33 (5) Seq. ID. 940 00 (>24) 00 (>24) 00 (>24) 32 (5) Seq. ID. 945 75 (9) 100 (0.5) 100 (0.5) 100 (0.5) Seq. ID.
  • OVX Rat Model In Vivo Anti-Osteoporosis Activity Testing in OVX Rat Model: The ovariectomised (OVX) rats were used to study anti-osteoporosis activity of test compounds (short-chain peptides) in vivo. The OVX rats develop osteopenia due to ovarian hormone deficiency. Osteopenia can be detected as early as 14 days post OVX, increase for the next 100 days and then stabilised (Wronski T. J., et al., Calcif. Tissue Int., 43(3), 1988, 179-183).
  • rats were bilaterally ovariectomised under anesthesia.
  • Ovariectomy Incision was made on dorsa-lateral side near lumbar region of animal. After that, ovary was excised and the veins were tied with ligature before removing ovary to prevent blood loss. Then incision was sutured back with ligature.
  • FIG. 1 The In vitro DRC study (in Rat PTH-1 R assay) data (EC 50 ) of PTH(1-34) (FIG. A) and Seq. ID No. 111 (FIG. B), as representative figure is shown in FIG. 1 .
  • FIG. 4 represents the Changes in biochemical parameters and femur weight, in OVX Rat after 6 weeks treatment with Seq. ID No. 111 and PTH(1-34).
  • the FIGS. 5 , 6 and 7 represents histological sections of the femur, tibia and lumbar vertebrae, in OVX rats, after 6-weeks treatment with Seq. ID No. 111.
  • the present invention provides a method of making short chain peptides that function as an agonist of the PTH-1 receptor having different degree of affinity (1-1000 nM concentration) in UMR-106 cells.
  • the PTH-1 receptor agonistic activity was assessed by estimation of amount of cAMP released by the test compounds (in vitro).
  • OVX mice/rat models in vivo
  • some of the short-chain peptides showed improvement in bone growth parameter thus making them ideal therapeutic candidates for the treatment and prevention of osteoporosis.
  • Novel short chain peptides of present invention showed increased stability against various proteolytic enzymes and due to increased stability and short chain length, such short chain peptides can also be delivered by oral route of administration, along with other invensive and non-invensive routes of administration.
  • novel short chain peptides of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients as are well known.
  • the pharmaceutical composition is provided by employing conventional techniques.
  • the composition is in unit dosage form containing an effective amount of the active component, that is, the short-chain peptides of formula (I) either alone or combination, according to this invention.
  • the pharmaceutical composition can be prepared by known processes by combining the compound of formula (I) with suitable excipients comprising suitable excipients selected from suitable diluents, stabilizers, buffers and the like as is known in the art.
  • the quantity of active component that is, the short chain peptides of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular short chain peptides and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
  • the short chain peptides of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating or preventing osteoporosis, such as primary osteoporosis, endocrine osteoporosis (hyperthyroidism, hyperparathyroidism, Cushing's syndrome, acromegaly, type 1 diabetes mellitus, adrenal insufficiency), hereditary and congenital forms of osteoporosis (osteogenesis imperfecta, homocystinuria, Menkes' syndrome and Riley-Day syndrome), nutritional and gastrointestinal disorders, haematological disorders/malignancy (multiple myeloma, lymphoma and leukaemia, hemophilia, thalassemia), osteoporosis due to immobilization, chronic obstructive pulmonary disease or rheumatologic disorders (rheumatoid arthritis, spondylitis), Osteomyelitis or an infectious le
  • Hypercalcemia resulting from solid tumours and hematologic malignancies idiopathic hypercalcemia and hypercalcemia associated with hyperthyroidism and renal function disorders.
  • Osteopenia following surgery induced by steroid administration and associated with disorders of the small and large intestine and with chronic hepatic and renal diseases.
  • Osteonecrosis or bone cell death associated with traumatic injury or nontraumatic necrosis associated with Gaucher's disease, sickle cell anaemia, systemic lupus erythematosus and other conditions.
  • Periodontal bone loss, Osteolytic metastasis, bone fracture healing and hyperproliferative skin disorders such as psoriasis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Rheumatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
US13/259,706 2009-04-24 2010-04-26 Short-chain peptides as parathyroid hormone (PTH) receptor agonist Expired - Fee Related US8383581B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IN1095MU2009 2009-04-24
IN1095/MUM/2009 2009-04-24
IN225/MUM/2010 2010-01-28
IN225MU2010 2010-01-28
PCT/IN2010/000264 WO2010128521A2 (en) 2009-04-24 2010-04-26 Short-chain peptides as parathyroid hormone (pth) receptor agonist

Publications (2)

Publication Number Publication Date
US20120108496A1 US20120108496A1 (en) 2012-05-03
US8383581B2 true US8383581B2 (en) 2013-02-26

Family

ID=43050579

Family Applications (1)

Application Number Title Priority Date Filing Date
US13/259,706 Expired - Fee Related US8383581B2 (en) 2009-04-24 2010-04-26 Short-chain peptides as parathyroid hormone (PTH) receptor agonist

Country Status (15)

Country Link
US (1) US8383581B2 (enExample)
EP (1) EP2421893A2 (enExample)
JP (1) JP5744844B2 (enExample)
KR (1) KR101451470B1 (enExample)
CN (1) CN102405229A (enExample)
AU (1) AU2010245642A1 (enExample)
BR (1) BRPI1008103A2 (enExample)
CA (1) CA2757874C (enExample)
EA (1) EA022212B1 (enExample)
IL (1) IL215625A (enExample)
MX (1) MX2011010968A (enExample)
NZ (1) NZ595437A (enExample)
SG (1) SG174532A1 (enExample)
WO (1) WO2010128521A2 (enExample)
ZA (1) ZA201107078B (enExample)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3928487A (en) * 1974-11-27 1975-12-23 Standard Oil Co Alkylation process utilizing hydrofluoric acid with a minor amount of fluorosulfuric acid

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY32099A (es) 2008-09-11 2010-04-30 Enanta Pharm Inc Inhibidores macrocíclicos de serina proteasas de hepatitis c
EP2658858A4 (en) 2010-12-30 2014-06-25 Enanta Pharm Inc MACROCYCLIC INHIBITORS OF HEPATITIS C SERINE PROTEASE PHENANTHRIDINE
MX2013007677A (es) 2010-12-30 2013-07-30 Abbvie Inc Inhibidores macrociclicos de serina proteasa de hepatitis.
WO2012120532A2 (en) 2011-02-02 2012-09-13 Cadila Healthcare Limited Cyclic short chain peptides
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
WO2015103490A1 (en) 2014-01-03 2015-07-09 Abbvie, Inc. Solid antiviral dosage forms
WO2024187241A1 (en) * 2023-03-16 2024-09-19 The Florey Institute Of Neuroscience And Mental Health Stapled peptides

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1447600A (en) 1998-10-22 2000-05-08 Thomas J. Gardella Bioactive peptides and peptide derivatives of parathyroid hormone (pth) and parathyroid hormone-related peptide (pthrp)
AU7734800A (en) * 1999-09-29 2001-04-30 General Hospital Corporation, The Polypeptide derivatives of parathyroid hormone (pth)
JP4723144B2 (ja) * 1999-09-29 2011-07-13 ザ ジェネラル ホスピタル コーポレイション 副甲状腺ホルモン（ｐｔｈ）のポリペプチド誘導体
CA2454275C (en) * 2001-07-23 2012-10-23 The General Hospital Corporation Conformationally constrained parathyroid hormone (pth) analogs
AU2002951372A0 (en) 2002-09-13 2002-09-26 St Vincent's Institute Of Medical Research Parathyroid hormone-like polypeptides
JP4541899B2 (ja) 2003-01-24 2010-09-08 ザ ジェネラル ホスピタル コーポレイション ラクタム架橋を有する、コンホメーションが制限された副甲状腺ホルモン（ｐｔｈ）アナログ
EP2201960A1 (en) * 2003-03-19 2010-06-30 The General Hospital Corporation Conformationally constrained parathyroid hormones with alpha-helix stabilizers
JP4871128B2 (ja) 2003-07-17 2012-02-08 ザ ジェネラル ホスピタル コーポレイション 高次構造的に制約された副甲状腺ホルモン（ｐｔｈ）アナログ
US20070123548A1 (en) 2004-02-11 2007-05-31 Cowan David J Pth agonists
JP2007522214A (ja) 2004-02-11 2007-08-09 スミスクライン・ビーチャム・コーポレイション Ｐｔｈアゴニスト
ITMI20041440A1 (it) 2004-07-19 2004-10-19 Abiogen Pharma Spa Peptidi analoghi del pth-1-11
CA2621264A1 (en) 2005-09-06 2007-11-15 Zelos Therapeutics, Inc. Parathyroid hormone analogues and methods of use
EP1961765A1 (en) 2006-12-08 2008-08-27 Zealand Pharma A/S Truncated PTH peptides with a cyclic conformation
MX353986B (es) * 2007-08-01 2017-11-06 Massachusetts Gen Hospital Metodos de analisis y seleccion usando receptores acoplados a proteina g y composiciones relacionadas.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Shimizu et al., Journal of Bone and Mineral Research (2004) vol. 19, No. 12, pp. 2078-2086. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3928487A (en) * 1974-11-27 1975-12-23 Standard Oil Co Alkylation process utilizing hydrofluoric acid with a minor amount of fluorosulfuric acid

Also Published As

Publication number Publication date
WO2010128521A3 (en) 2011-03-10
KR101451470B1 (ko) 2014-10-15
JP2012524775A (ja) 2012-10-18
CN102405229A (zh) 2012-04-04
IL215625A (en) 2016-12-29
WO2010128521A2 (en) 2010-11-11
EA022212B1 (ru) 2015-11-30
EA201171292A1 (ru) 2012-05-30
AU2010245642A1 (en) 2011-10-27
CA2757874C (en) 2016-02-16
KR20120034606A (ko) 2012-04-12
BRPI1008103A2 (pt) 2016-05-03
NZ595437A (en) 2014-03-28
EP2421893A2 (en) 2012-02-29
MX2011010968A (es) 2012-01-19
IL215625A0 (en) 2012-01-31
JP5744844B2 (ja) 2015-07-08
SG174532A1 (en) 2011-10-28
CA2757874A1 (en) 2010-11-11
ZA201107078B (en) 2014-03-26
US20120108496A1 (en) 2012-05-03

Similar Documents

Publication Publication Date Title
US8383581B2 (en) Short-chain peptides as parathyroid hormone (PTH) receptor agonist
Bourgault et al. Novel stable PACAP analogs with potent activity towards the PAC1 receptor
FI104253B (fi) Menetelmä terapeuttisesti käyttökelpoisten nonapeptidibombesiiniantagonistien valmistamiseksi
SK155694A3 (en) Glucagon-like peptide, insulinotropin derivatives, method of their preparation, pharmaceutical agent containing and using these matters
JP4541899B2 (ja) ラクタム架橋を有する、コンホメーションが制限された副甲状腺ホルモン（ｐｔｈ）アナログ
WO2014049610A2 (en) Peptides as gip, glp-1 and glucagon receptors triple-agonist
JP2010539132A (ja) アミリンの改良された誘導体
CA2403447A1 (en) Peptide derivative
CN102596228A (zh) 神经肽-2受体(y-2r)激动剂
JP2007528836A (ja) α−ヘリックス安定化剤を用いる高次構造的に制約された副甲状腺ホルモン
JPH10510814A (ja) ベタイドを製造するためのアミノ酸並びにベタイドライブラリーのスクリーニング方法及び製造方法
KR101108354B1 (ko) Ｐｔｈ 수용체 조절제로서의 페길화된 ｐｔｈ 및 그의 용도
HUT69708A (en) Process for producing parathormon fragments and pharmaceutical compositions containing them
KR20010085847A (ko) 펩티드 유도체
EP0773958A1 (en) PTH OR PTHrP ANTAGONISTS
US20110195900A1 (en) Peptidic pth receptor agonists
WO2012120532A2 (en) Cyclic short chain peptides
JPH0641194A (ja) ソマトスタチン類似体
KR20250140094A (ko) Gip/glp1/gcg 삼중-수용체 효능제 및 그의 용도
CA2606894A1 (en) Novel compounds as glp-i agonists
JPH07316195A (ja) 新規なＰＴＨｒＰ関連ペプチド及びその用途
AU736207B2 (en) Peptides which promote activation of latent TGF-beta and method of screening TGF-beta activity-regulating compounds
SK3893A3 (en) Bombesine antagonists
EP4545553A2 (en) Peptide compound and application thereof, and composition containing peptide compound
Rajeswaran et al. Exploration of the DTrp-NMeLys motif in the search for potent somatostatin antagonists

Legal Events

Date Code Title Description
AS Assignment

Owner name: CADILA HEALTHCARE LIMITED, INDIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BAHEKAR, RAJESH;JAIN, MUKUL R.;PATEL, PANKAJ R.;REEL/FRAME:027505/0707

Effective date: 20111209

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20210226